Tahara H, Imanishi Y, Yamada T, Tsujimoto Y, Tabata T, Inoue T, Inaba M, Morii H, Nishizawa Y
Department of Internal Medicine, Osaka City University Graduate School of Medicine, Japan.
J Clin Endocrinol Metab. 2000 Nov;85(11):4113-7. doi: 10.1210/jcem.85.11.6950.
The molecular pathway of autonomous growth of the parathyroid glands in uremic patients is poorly understood. Loss of heterozygosity at the recently identified multiple endocrine neoplasia type 1 (MEN1) gene locus on chromosome 11q13 has been found in a subset of parathyroid glands from patients with refractory hyperparathyroidism. To clarify the role of the MEN1 gene in parathyroid tumorigenesis, we analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, D11S4946, and D11S449) and for mutations of the MEN1-coding exons by PCR-based single strand conformation polymorphism analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion (331delG) of the MEN1 gene. This mutation would probably result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathological characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. These observations indicate that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited.
尿毒症患者甲状旁腺自主生长的分子途径目前了解甚少。在难治性甲状旁腺功能亢进患者的一部分甲状旁腺中，发现位于11号染色体长臂11q13上最近确定的多发性内分泌肿瘤1型（MEN1）基因座存在杂合性缺失。为阐明MEN1基因在甲状旁腺肿瘤发生中的作用，我们使用3个侧翼标记（PYGM、D11S4946和D11S449）对22例日本尿毒症患者的81个甲状旁腺进行11q13染色体臂DNA等位基因缺失分析，并通过基于聚合酶链反应的单链构象多态性分析和测序对MEN1编码外显子的突变进行检测。在6个腺体（7%）中观察到11q13等位基因缺失，其中1个显示出MEN1基因先前未被识别的体细胞移码缺失（331delG）。该突变可能导致无功能的menin蛋白，这与肿瘤抑制机制一致。甲状旁腺功能亢进的临床和病理特征与11q13杂合性缺失和MEN1基因突变的有无无关。这些观察结果表明，MEN1基因的体细胞失活参与了尿毒症相关甲状旁腺肿瘤的发病机制，但其在该疾病中的作用似乎非常有限。
